Scientific article
Open access

Cell-specific alterations in Pitx1 regulatory landscape activation caused by the loss of a single enhancer

Published inNature communications, vol. 12, no. 1, 7235
Publication date2021-12-13
First online date2021-12-13

Developmental genes are frequently controlled by multiple enhancers sharing similar specificities. As a result, deletions of such regulatory elements have often failed to reveal their full function. Here, we use the Pitx1 testbed locus to characterize in detail the regulatory and cellular identity alterations following the deletion of one of its enhancers (Pen). By combining single cell transcriptomics and an in-embryo cell tracing approach, we observe an increased fraction of Pitx1 non/low-expressing cells and a decreased fraction of Pitx1 high-expressing cells. We find that the over-representation of Pitx1 non/low-expressing cells originates from a failure of the Pitx1 locus to coordinate enhancer activities and 3D chromatin changes. This locus mis-activation induces a localized heterochrony and a concurrent loss of irregular connective tissue, eventually leading to a clubfoot phenotype. This data suggests that, in some cases, redundant enhancers may be used to locally enforce a robust activation of their host regulatory landscapes.

  • Acetylation
  • Animals
  • Chromatin / chemistry
  • Chromatin / metabolism
  • Connective Tissue / growth & development
  • Connective Tissue / metabolism
  • Embryo, Mammalian
  • Enhancer Elements, Genetic / genetics
  • Epigenesis, Genetic
  • Gene Expression Regulation, Developmental
  • Hindlimb / cytology
  • Hindlimb / embryology
  • Hindlimb / metabolism
  • Limb Buds / cytology
  • Limb Buds / embryology
  • Limb Buds / metabolism
  • Mice
  • Models, Genetic
  • Paired Box Transcription Factors / genetics
  • Paired Box Transcription Factors / metabolism
  • Sequence Deletion
Citation (ISO format)
ROUCO, Raquel et al. Cell-specific alterations in Pitx1 regulatory landscape activation caused by the loss of a single enhancer. In: Nature communications, 2021, vol. 12, n° 1, p. 7235. doi: 10.1038/s41467-021-27492-1
Main files (1)
Article (Published version)
ISSN of the journal2041-1723

Technical informations

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